Materials used in the manufacture of medical devices which are to be used in contact with protein-containing or biological fluids are selected on the basis of acceptable physical and mechanical properties and compatibility with the protein-containing or biological fluid. However, it is often difficult to optimise all of these properties simultaneously and so a compromise must be reached which often results in sub-optimal performance.
As an example, early gas permeable contact lenses were formed from silicones and, as a consequence, had a very low water content and were relatively rigid. The hydrophobic nature of silicone materials meant that the lenses were poorly wettable and had a tendency to stick to the eye. Furthermore, while lenses formed from silicones have a high oxygen permeability, the low water content of such materials means that they can be uncomfortable for the wearer. Hence, the focus then shifted to hydrogel systems incorporating hydrophilic monomers such as 2-hydroxyethylmethacrylate (HEMA), N-vinyl pyrrolidone and methacrylic acid. Hydrogel systems have a significant water content, frequently above 30%, and, as a result, are more comfortable for the wearer. However, the oxygen permeability of these materials generally is not as high as it is for silicones which increases the risk of damage to the eye as a result of hypoxia. In this regard, the oxygen permeability of these hydrogel lenses may be sufficient for daily use but is not generally suitable for extended wear.
Therefore, more recently, the focus has been on developing materials with a balance of properties, primarily the oxygen permeability associated with silicone materials, and the water content, wettability and lower modulus associated with hydrogel systems. Achieving the correct balance of properties is important to ensure minimum risk to ocular health and good tear film stability which is essential for comfort. Currently the materials of choice are silicone hydrogels, although these are not ideal because, although they contain water, the materials are inherently hydrophobic and are poorly wettable. Efforts have been made to improve the wettability of these materials. For example, manufacturers have used plasma treatments to modify surface properties in order to increase surface wettability. However, a disadvantage of such approaches is that it introduces additional steps in to the manufacturing process which may be difficult to control.
Clearly, as the contact lenses will be in contact with the surface of the eye, a further important consideration is the biocompatibility of the lens material. It is of utmost importance that the silicone hydrogels used to form contact lenses do not elicit any unwanted biological response. As silicone materials are inherently hydrophobic this is a particular challenge because hydrophobicity causes the tear film of the eye to break up leading to discomfort, and in addition, may encourage the deposition of tear film components such as proteins and lipids Hence, there is a need for biocompatible materials which provide biocompatibility together with both high gas, in particular oxygen, permeability and an appropriate water content and surface wettability to provide a lens with suitable mechanical properties and level of on-eye comfort.
As described above, polymerisable ethylenically unsaturated components, such as methacrylic acid and ester derivatives thereof, have been used to manufacture ophthalmic lenses, and much effort has been devoted to copolymerise such unsaturated systems with biocompatible co-monomers to produce lens materials with improved biocompatibility. Polymerisable zwitterionic materials, in particular, 2-(methacryloyloxyethyl)-2′(trimethylammonium ethyl)phosphate, inner salt (MPC), have been used to form biocompatible polymers. These materials contain the zwitterionic phosphorylcholine (PC) group and the biocompatibility of these materials is derived from the fact that this PC group mimics the zwitterionic structure of phospholipids such as phosphatidylcholine and sphingomyelin which are the major components of the outer membrane of all living cells. Contact lens materials incorporating MPC (EP 0555295) have been shown to possess beneficial properties, including reduced dehydration on eye and reduced deposition of tear film components (Guillon J P, et al., Adv. Exp. Med. Biol, 2002, 506 (Part B), 901-15). More generally, polymers containing zwitterionic groups have been shown to improve biocompatibility by reducing protein deposition, blood activation, inflammatory reactions, bacterial adhesion and inhibiting biofilm formation (see Lewis, A L, Colloids and Surfaces B: Biointerfaces 18 (2000) 261-275, and references therein).
However, a disadvantage of MPC and related zwitterionic materials is that they are frequently solids with very limited solubility. This places limitations on the utility of MPC and other zwitterions as components in lens formulations. Indeed, to date, the incorporation of these zwitterionic monomers into silicone hydrogel formulations which comprise siloxane co-monomers has not been possible due to the inherent poor solubility of MPC in these liquid co-monomers and the tendency of the derived siloxane-zwitterion polymers to be opaque due to microphase separation.
Accordingly, there is a need for a method by means of which it is possible to incorporate zwitterionic monomers, in particular MPC, into mixtures containing monomer units having a siloxane functionality, thus making it possible to produce polymers useful for forming ophthalmic devices, in particular contact lenses with beneficial properties.
Against this background, the present invention provides a method for producing a polymerisable solution which can be polymerised to produce a polymer which comprises both a zwitterionic functionality and a siloxane functionality.
Accordingly, in a first aspect, the present invention provides a method which comprises dissolving an ethylenically unsaturated zwitterionic monomer in a co-monomer system comprising a functionalised ethylenically unsaturated solubilising monomer in which the zwitterionic monomer is soluble, a siloxane group-containing monomer or macromer, and a cross-linking agent, to produce a polymerisable solution.
As described above, ethylenically unsaturated zwitterionic monomers, such as MPC are insoluble in many of the commonly used liquid components used to form silicone hydrogels. In addition, attempts to polymerise such compositions results in microphase separation, leading to opaque polymers, unsuitable for use as ophthalmic devices. However, the present inventors have found that it is possible to dissolve an ethylenically unsaturated zwitterionic monomer, for example MPC, in a suitable functionalised ethylenically unsaturated solubilising monomer such as HEMA or other suitable solubilising monomer to produce a solution, and by careful selection of the nature and content of the components present in the co-monomer system, thus overcome these problems.
In particular, it is possible to incorporate zwitterionic monomers into formulations containing siloxane components, wherein the resulting polymerisable solution is clear and which produces a clear polymer after polymerisation and after hydration of the polymer to form the hydrogel. Furthermore, because the functionalised ethylenically unsaturated solubilising monomer can be a component such as HEMA, glycerylmethacrylate (GMA) or methacrylic acid which may be desirable for inclusion into a polymer which will ultimately be used in an ophthalmic application, the method does not require the addition of non-reactive solvating components which would not so conveniently be present in the formation of such polymers. Therefore, it is not necessary for the method to be complicated by further steps in which it is necessary to remove the solvent which has been used to solubilise the ethylenically unsaturated zwitterionic monomer.
A further advantage is that the material which results from polymerisation and subsequent hydration of the polymerisable solution obtainable by the method of the present invention is also clear and homogeneous.
The method of the present invention involves dissolving the zwitterionic monomer in a co-monomer system which comprises a functionalised ethylenically unsaturated solubilising monomer in which the zwitterionic monomer is soluble, a siloxane group-containing monomer or macromer, and a cross-linking agent. The result is a polymerisable solution which is homogeneous. The term “homogeneous” is used herein to describe a solution which is a single phase i.e. a solution which appears visibly to consist of a single phase. The fact that a homogeneous solution may be obtained is surprising given that a hydrophilic component (the zwitterionic monomer) is being mixed with a hydrophobic component (the siloxane group-containing monomer or macromer).
The ethylenically unsaturated zwitterionic monomer which is dissolved in the co-solvent system is a monomer which comprises an ethylenically unsaturated group and a zwitterionic group. In one embodiment, the ethylenically unsaturated zwitterionic monomer is a monomer of formula (I):
wherein:J is selected from the group consisting of                a valence bond;        —W—X—Y—, wherein W is (CR12)n; X is O, S or NR2 and Y is a linker group; and        —K—X—Y—, wherein K is (CR12)nC(O); X is O, S or NR2 and Y is a linker group;Z is a zwitterionic group;each R1 is independently selected from H, halogen, C1-4 alkyl or C1-4 haloalkyl;R2 is H or C1-4 alkyl;n is an integer from 0 to 6; andm is an integer from 0 to 6.        
Although formula (I) (and the chemical formulae which follow herein) are represented without any indication of specific stereochemistry, the skilled person will understand that a number of possible isomers are possible. In this regard, the present invention includes within its scope, all possible stereoisomers of the chemical structures depicted.
In one embodiment, the ethylenically unsaturated zwitterionic monomer is a monomer of formula (I), wherein J is a valence bond, each R1 is hydrogen and m is 1.
In one embodiment, the ethylenically unsaturated zwitterionic monomer is a monomer of formula (II):
wherein W, X, Y, Z, R1 and m are as defined above.
The value of n may be 0, 1, 2, 3, 4, 5 or 6. In a preferred embodiment, n is 0. In an alternative embodiment, n is 1. In a further embodiment, n is 2. Where n is 0, the vinyl group is adjacent to the heteroatom which means that the lone pair of electrons on the heteroatom can interact with the electrons in the vinyl group which has the effect of increasing the reactivity of the monomer.
In one embodiment, R1 is hydrogen. In an alternative embodiment, R1 is C1-4 alkyl, in particular ethyl or methyl, in particular methyl. In an alternative embodiment, R1 may be halogen, in particular fluorine. In an alternative embodiment, R1 may be a C1-4 haloalkyl group, wherein one or more of the hydrogen atoms in the alkyl group is substituted with a halogen, in particular fluorine. An example of a C1-4 haloalkyl group is CF3. Each R1 group may be the same or different. In one embodiment, the R1 groups are different. In one embodiment, the R1 groups are the same. For example, when n is 1, each of the two R1 groups bound to the carbon atom may be the same or different. Similarly, when n is 2, each of the four R1 groups may be the same or different. Similarly, when n is 1 and m is 1, each of the four R1 groups may be the same or different.
In one embodiment, X is O. In alternative embodiment, X is S. In a further embodiment, X is NR2. In one embodiment, R2 is hydrogen. In one embodiment, R2 is C1-4 alkyl, in particular ethyl or methyl, in particular methyl.
Y is a linker group which forms a link between the heteroatom X and the (CR12)mZ group in the monomer of formula (I) or formula (II). The nature of group Y is not particularly limited and in a preferred embodiment, Y is selected from the group consisting of C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene, C3-10 cycloalkylene, C3-10 cycloalkenylene, C1-10 heteroalkylene, C2-10 heteroalkenylene, C2-10 heteroalkynylene, arylene, heteroarylene, —C(O)—, —C(S)—, —C(O)O—, —C(O)S—, —C(O)N(RM)—, —C(S)—, —C(S)O—, —C(S)S— and —C(S)N(RM)—, wherein RM is hydrogen or C1-4 alkyl. The alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, heteroalkylene, heteroalkenylene, heteroalkynylene, arylene and heteroarylene groups may be optionally substituted with one or more RN, wherein each RN is independently selected from the group consisting of —H, —OH, —CN, —NO2, —CF3, —OCF3, —CO2H, —NH2, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, —O(C1-C10 alkyl), —O(C2-C10 alkenyl), —O(C2-C10 alkynyl), halogen, —C(O)H, —C(O)—(C1-C10 alkyl), —C(O)—O(C1-C10 alkyl), —NH(C1-C10 alkyl), —N(C1-C10 alkyl)2, —C(O)—NH(C1-C10 alkyl), —C(O)—N(C1-C10 alkyl)2, —NH—C(O)—(C1-C10 alkyl), —NH(C1-C10 alkyl)-C(O)—(C1-C10 alkyl), —NH—S(O)2—(C1-C10 alkyl), —NH—(C1-C10 alkyl)-S(O)2—(C1-C10 alkyl), —(C0-C10)—SH, —S(O)—(C1-C10 alkyl), —S(O)2—(C1-C10 alkyl), —S(O)2—NH2, —S(O)2—NH—(C1-C10 alkyl), —S(O)2—N(C1-C10 alkyl)2 and ═O.
In one embodiment, Y is a C1-10 alkylene, C2-10 alkenylene or C2-10 alkynylene optionally substituted with one or more RN. In a further embodiment, Y is C1-6 alkylene, C2-6 alkenylene or C2-6 alkynylene optionally substituted with one or more RN. In a further embodiment, Y is C1-10 alkylene, in one instance C1-6 alkylene optionally substituted with one or more RN.
In an alternative embodiment, Y is —C(═V)A-, wherein V is S or O and A is selected from NRM, O or S, wherein RM is H or C1-4 alkyl. In particular, in one embodiment, the present invention provides a monomer of formula (IB):
wherein W, X and Z, R1, R2, n and m are as defined above in connection with formula (I), V is S or O; and A is selected from NRM, O and S. Where the monomer of the present invention has formula (IB), preferably V is O and A is O such that Y as defined in formula (I) and formula (II) is —C(O)O—.
In the monomers of formula (I) and formula (II) wherein X is selected from NR2, then R2, Y and the N atom to which they are bonded taken together may form a 5 to 7 membered heterocyclic ring optionally substituted with one or more RN, particularly wherein RN is O. In particular, R2, Y and the N atom to which they are bonded taken together form a 5-membered heterocyclic ring be optionally substituted with one or more RN, particularly wherein RN is O.
In one embodiment, the monomer has the formula (IA):
wherein W, R1 and Z are as defined above. In one embodiment, the monomer has the formula (IA), wherein n is 0 and hence the group W is not present.
In the monomers of formula (I), (IA), (IB) and (II), the value of m may be 0, 1, 2, 3, 4, 5 or 6. In one embodiment, m is 0.
In particular, in a monomer of formula (II), preferably m is 0 when Y is a group as defined above other than —C(O)—, —C(S)—, —C(O)O—, —C(O)S—, —C(O)N(RM)—, —C(S)— or —C(S)N(RM)—. In an alternative embodiment, in particular where Y is —C(O)—, —C(S)—, —C(O)O—, —C(O)S—, —C(O)N(RM)—, —C(S)— or —C(S)N(RM)—, m is 1 or 2.
In one embodiment, the ethylenically unsaturated zwitterionic monomer is an acrylic zwitterionic monomer of formula (ID):
wherein R1, X, Z and m are as defined above.
In a preferred embodiment, the ethylenically unsaturated zwitterionic monomer is a monomer of formula (ID), wherein R1 is methyl, X is O and m is 2.
In one embodiment, the ethylenically unsaturated zwitterionic monomer is a poly(ethylene glycol) derivative zwitterionic monomer of formula (III):
wherein R1, J and Z are as defined above and mm is an integer in the range from 1 to 20. Preferably, mm is an integer in the range from 1 to 10.
In one embodiment, the ethylenically unsaturated zwitterionic monomer is a poly(ethylene glycol) derivative zwitterionic monomer of formula (IIIA):

In one embodiment, the ethylenically unsaturated zwitterionic monomer is a poly(ethylene glycol) derivative zwitterionic monomer of formula (IIIB):
wherein Z is a group of formula (IVB) as defined below, wherein all R4 groups are methyl and b is 2.
Z is a zwitterionic group. A zwitterionic group is one which carries both a positive charge and a negative charge located on different atoms within the group such that the net charge of the group is zero. As a consequence, zwitterionic groups have a high polarity and a natural affinity for water. Phospholipids, such as phosphatidylcholine and sphingomyelin, which are the major components of the outer membrane of all living cells have a zwitterionic structure. Hence, the acrylic zwitterionic monomers can be used to produce polymers which mimic the zwitterionic structure of phospholipids. This results in the biocompatibility of the polymers which may be produced.
In one embodiment, Z is a zwitterionic group selected from the group consisting of formula (IVA), (IVB), (IVC), (IVD) and (IVE).
Preferably, Z is a zwitterionic group of formula (IVB).
Group (IVA) has the formula:
wherein each R3 and R3A is independently selected from hydrogen and C1-4 alkyl and a is an integer from 2 to 4.
In one embodiment, both R3 groups are the same. In particular, both R3 groups may be C1-4 alkyl, in one embodiment, methyl.
In one embodiment, both R3A groups are the same. In particular, both R3A groups may be hydrogen.
In one embodiment, a is 2 or 3. In a further embodiment, a is 3.
In one embodiment where Z is a group of formula (IVA), m is 1 or 2.
Group (IVB) has the formula:
wherein each R4 and R4A is independently selected from hydrogen and C1-4 alkyl and b is an integer from 1 to 4;
In one embodiment, all R4 groups are the same. In particular, all R4 groups may be C1-4 alkyl, in one embodiment, methyl. In one embodiment, at least one R4 group is C1-4 alkyl.
In one embodiment, the R4A groups are the same. In particular, the R4A groups may be hydrogen.
In one embodiment, b is 2 or 3. In a further embodiment, b is 2.
In one embodiment where Z is a group of formula (IVB), m in formula (I) is 1 or 2.
In one embodiment, preferably Z is a group of formula (IVB), wherein all R4 groups are methyl groups and b is 2. In this embodiment, Z is a phosphorylcholine (PC) group. PC groups occur naturally in the phospholipids which form the membranes of all living cells. Therefore, with a view to mimicking the zwitterionic properties of phospholipids, it is particularly advantageous for Z to be a PC group.
Group (IVC) has the formula:
wherein each R5 and R5C is independently selected from hydrogen and C1-4 alkyl; R5A is hydrogen or a group —C(O)B1R5B, wherein R5B is hydrogen or methyl, B1 is selected from the group consisting of a bond; C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene, C3-10 cycloalkylene, C3-10 cycloalkenylene, C1-10 heteroalkylene, C2-10 heteroalkenylene, C2-10 heteroalkynylene, arylene, heteroarylene, wherein the alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, heteroalkylene, heteroalkenylene, heteroalkynylene, arylene and heteroarylene groups may be optionally substituted with one or more RN as defined previously, and c is an integer from 1 to 4, wherein if Z is directly bonded to an O or N atom, z is 0 and otherwise z is 1.
In one embodiment, the R5 groups are the same. In particular, the R5 groups may be C1-4 alkyl, in one embodiment, methyl. In one embodiment, at least one R5 group is C1-4 alkyl.
In one embodiment, both R5C groups are the same. In particular, the R5C groups may be hydrogen.
In one embodiment, c is 2 or 3. In a further embodiment, c is 3.
Group (IVD) has the formula:
wherein each R6 and R6C is independently selected from hydrogen and C1-4 alkyl; R6A is hydrogen or a group —C(O)B2R6B, wherein R6B is hydrogen or methyl, B2 is selected from the group consisting of a bond; C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene, C3-10 cycloalkylene, C3-10 cycloalkenylene, C1-10 heteroalkylene, C2-10 heteroalkenylene, C2-10 heteroalkynylene, arylene, heteroarylene, wherein the alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, heteroalkylene, heteroalkenylene, heteroalkynylene, arylene and heteroarylene groups may be optionally substituted with one or more RN as defined previously, and d is an integer from 1 to 4, wherein if Z is directly bonded to an O or N atom, z is 0 and otherwise z is 1;
In one embodiment, the R6 groups are the same. In particular, the R6 groups may be C1-4 alkyl, in one embodiment, methyl. In one embodiment, at least one R6 group is C1-4 alkyl.
In one embodiment, both R6C groups are the same. In particular, the R6C groups may be hydrogen.
In one embodiment, d is 1 or 2. In a further embodiment, d is 2.
Group (IVE) has the formula:
wherein each R7 and R7C is independently selected from hydrogen and C1-4 alkyl; R7A is hydrogen or a group —C(O)B2R7B, wherein R7B is hydrogen or methyl, B2 is selected from the group consisting of a bond; C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene, C3-10 cycloalkylene, C3-10 cycloalkenylene, C1-10 heteroalkylene, C2-10 heteroalkenylene, C2-10 heteroalkynylene, arylene, heteroarylene, wherein the alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, heteroalkylene, heteroalkenylene, heteroalkynylene, arylene and heteroarylene groups may be optionally substituted with one or more RN as defined previously, and e is an integer from 1 to 4, wherein if Z is directly bonded to an O or N atom, z is 0 and otherwise z is 1;
In one embodiment, the R7 groups are the same. In particular, the R7 groups may be C1-4 alkyl, in one embodiment, methyl. In one embodiment, at least one R7 group is C1-4 alkyl.
In one embodiment, both R7C groups are the same. In particular, the R7C groups may be hydrogen.
In one embodiment, e is 1 or 2. In a further embodiment, e is 2.
Preferably, Z is a group of formula (IVB), in particular, a group of formula (IVB), wherein all R4 groups are methyl groups and b is 2. In a particularly preferred embodiment, the ethylenically unsaturated zwitterionic monomer is a monomer of formula (ID), wherein R1 is methyl, X is O, m is 2 and Z is a group of formula (IVB), wherein all R4 groups are methyl groups and b is 2. In this embodiment, the ethylenically unsaturated zwitterionic monomer is 2-(methacryloyloxyethyl)-2′(trimethylammonium ethyl)phosphate, inner salt (MPC) (also known as hydroxyethyl methacrylate-phosphorylcholine, HEMA-PC).
An essential component of the co-solvent system in which the ethylenically unsaturated zwitterionic monomer is dissolved is a functionalised ethylenically unsaturated solubilising monomer in which the zwitterionic monomer is soluble. This ensures that a clear homogeneous polymerisable solution is obtained. The term “functionalised” is used herein to mean that the ethylenically unsaturated monomer has a terminal functional group, wherein the functional group is selected from the group consisting of —OH, —NRP2, —C(O)ORP and —C(O)NRP2, wherein each RP is independently selected from H and C1-6 alkyl. In one embodiment, the functionalised ethylenically unsaturated solubilising monomer is a hydroxylated ethylenically unsaturated monomer.
Preferably, the functionalised ethylenically unsaturated solubilising monomer is an acrylic acid or ester thereof. Examples include methacrylic acid, acrylic acid, hydroxybutyl methacrylate, hydroxypropyl methacrylate, hydroxybutyl acrylate, hydroxypropyl acrylate, hydroxyethyl methacrylate (HEMA), hydroxyethyl acrylate and glycerol methacrylate (GMA).
Preferably the functionalised ethylenically unsaturated solubilising monomer is hydroxyethylmethacrylate (HEMA) or glycerol methacrylate (GMA). However, although the description which follows focuses on HEMA or GMA, the descriptions apply equally to other functionalised ethylenically unsaturated solubilising monomers in which the zwitterionic monomer is soluble.
As used herein, the term “soluble” means that the zwitterionic monomer forms a mixture with the functionalised ethylenically unsaturated solubilising monomer wherein the mixture exhibits the same or substantially the same values of physical properties throughout the mixture, i.e. the mixture comprises an essentially single phase and/or is essentially homogeneous. Conveniently, solubility can be assessed by light scattering. For a monomer A which is soluble in monomer B, the addition of monomer A to monomer B results in essentially no change in light scattering. An essentially single phase mixture is characterised by high optical clarity. The boundary between an essentially single phase mixture and a mixture with two (or more) phases is defined by the “cloud point” which, for a given monomer blend, is defined as the temperature at which phase separation is observed. Clarity may be assessed on the macro-scale by eye.
In some embodiments, dissolution of the ethylenically unsaturated zwitterionic monomer in the co-monomer system may be accelerated by agitation such as stirring and/or shaking. Heat may also be applied, although care must be taken to control the temperature such that premature polymerisation does not occur.
In one embodiment of the method of the present invention, the speed of dissolution of the ethylenically unsaturated zwitterionic monomer in the co-solvent system may be accelerated by pre-dissolving the ethylenically unsaturated zwitterionic monomer in the functionalised ethylenically unsaturated solubilising monomer in which is it soluble prior to mixing with the other components of the co-monomer system.
The other essential components which comprise the co-monomer system in which the zwitterionic monomer is dissolved are a siloxane group-containing monomer or macromer and a cross-linking agent. In this regard, the co-monomer system comprises components which are used conventionally to form silicone hydrogel polymers useful in the production of ophthalmic devices.
The term “macromer” is used to refer to a low molecular weight polymer having at least one polymerisable end group and a degree of polymerisation (DP) ranging from 2 to 1000 monomeric repeat units and/or having a number average molecular weight range from approximately 100 to 100,000 Daltons.
It is the presence of the siloxane groups in the polymers which can be synthesized from the polymerisable solution which is made by the method of the present invention which contributes to high oxygen permeability, an important consideration for ophthalmic devices, in particular contact lenses. However, the hydrophobic nature of siloxane components has, to date, resulted in microphase separation when attempts have been made to incorporate zwitterionic monomers. This is a problem which has been overcome by the method of the present invention.
A siloxane group-containing component is one which includes the residue having the general structure —[Si(R)2O]—, wherein R is hydrogen or a C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene, C3-10 cycloalkylene, C3-10 cycloalkenylene, C1-10 heteroalkylene, C2-10 heteroalkenylene, C2-10 heteroalkynylene, arylene, heteroarylene group. Preferably R is a C1-10 alkylene group, preferably a C1 alkylene group. Preferably, the Si and attached O are present in the siloxane group-containing monomer or macromer in an amount greater than 20 weight percent, and more preferably greater than 30 weight percent of the total molecular weight of the siloxane group-containing monomer or macromer.
Useful siloxane group-containing monomer or macromer may comprise polymerizable functional groups such as acrylate, methacrylate, acrylamide, methacrylamide, N-vinyl lactam, N-vinylamide, and styryl functional groups. Examples of siloxane group-containing components which may be included in the co-solvent system are described in U.S. Pat. No. 3,808,178, U.S. Pat. No. 4,120,570, U.S. Pat. No. 4,136,250, U.S. Pat. No. 4,153,641, U.S. Pat. No. 4,740,533, U.S. Pat. No. 5,034,461, U.S. Pat. No. 5,070,215 and EP 080539. All of the patents cited herein are hereby incorporated in their entireties by reference.
In one embodiment of the present invention, the siloxane group-containing monomer may be a polysiloxanylalkyl(meth)acrylic monomer represented by the following formula X:
wherein: T denotes H or lower alkyl and in certain embodiments H or methyl; Q denotes O or NR12; each R12 independently denotes hydrogen or methyl, each R8, R9 and R10 independently denotes a lower alkyl radical or a phenyl radical, and j is 1 or 3 to 10. Examples of these polysiloxanylalkyl(meth)acrylic monomers include methacryloxypropyl tris(trimethylsiloxy)silane, pentamethyldisiloxanyl methylmethacrylate, and methyldi(trimethylsiloxy)methacryloxymethyl silane.
An alternative class of siloxane group-containing components which may form a part of the co-solvent system are poly(organosiloxane) prepolymers represented by Formula XI:
wherein: each A′ independently denotes an activated unsaturated group, such as an ester or amide of an acrylic or a methacrylic acid or an alkyl or aryl group (providing that at least one A′ comprises an activated unsaturated group capable of undergoing radical polymerization); each of R14, R15, R16 and R17 are independently selected from the group consisting of a monovalent hydrocarbon radical or a halogen substituted monovalent hydrocarbon radical having 1 to 18 carbon atoms which may have ether linkages between carbon atoms; R13 denotes a divalent hydrocarbon radical having from 1 to 22 carbon atoms, and n′ is 0 or an integer greater than or equal to 1, in one embodiment n′ is 5 to 400, in another embodiment n′ is 10 to 300. One specific example is α,ω-bismethacryloxypropyl poly-dimethylsiloxane. Another example is mPDMS (monomethacryloxypropyl terminated mono-n-butyl terminated polydimethylsiloxane).
Another useful class of siloxane group-containing components includes silicone-containing vinyl carbonate or vinyl carbamate monomers of the following formula XII:
wherein: X′ denotes O, S or NH; RSi denotes a silicone-containing organic radical; T denotes hydrogen or lower alkyl, in certain embodiments H or methyl; t is 1, 2, 3 or 4; and q′ is 0 or 1. Suitable silicone-containing organic radicals RSi include the following:
wherein R18 denotes

Wherein p′ is 1 to 6; or an alkyl radical or a fluoro-alkyl radical having 1 to 6 carbon atoms; r′ is 1 to 200, t′ is 1, 2, 3 or 4; and s is 0, 1, 2, 3, 4 or 5.
The siloxane group-containing vinyl carbonate or vinyl carbamate monomers
specifically include: 1,3-bis[4-(vinyloxycarbonyloxy)but-1-yl]tetramethyl-isiloxane 3-(vinyloxycarbonylthio) propyl-[tris(trimethylsiloxysilane]; 3-[tris(trimethylsiloxy)silyl]propyl allyl carbamate; 3-[tris(trimethylsiloxy)wilyl]propyl vinyl carbamate; trimethylsilylethyl vinyl carbonate; trimethylsilylmethyl vinyl carbonate, and

Another class of silicone-containing components includes compounds of the following formulae:(*D*L*D*G)aa*D*D*E1;E(*D*G*D*L)aa*D*G*D*E1 or;E(*D*L*D*G)aa*D*L*D*E1  (Formulae XIII-XV)wherein:D denotes an alkyl diradical, an alkyl cycloalkyl diradical, a cycloalkyl diradical, an aryl diradical or an alkylaryl diradical having 6 to 30 carbon atoms,G denotes an alkyl diradical, a cycloalkyl diradical, an alkyl cycloalkyl diradical, an aryl diradical or an alkylaryl diradical having 1 to 40 carbon atoms and which may contain ether, thio or amine linkages in the main chain;* denotes a urethane or ureido linkage;aa is an integer of at least 1;L denotes a divalent polymeric radical of formula XVI:
in which R11 independently denotes an alkyl or fluoro-substituted alkyl group having 1 to 10 carbon atoms which may contain ether linkages between carbon atoms; r is at least 1; and p provides a moiety weight of 400 to 10,000; each of E and E1 independently denotes a polymerizable unsaturated organic radical represented by formula XVII:
wherein R19 is hydrogen or methyl; R20 is hydrogen, an alkyl radical having 1 to 6 carbon atoms, or a —CO—V′—R22 radical wherein V′ is —O—, —S— or —NH— and R22 is hydrogen or an alkyl radical having 1 to 6 carbon atoms; R21 is a divalent radical having 1 to 12 carbon atoms; Y′ denotes —CO— or —OCO—; W′ denotes —O— or —NH—; Ar denotes an aromatic radical having 6 to 10 carbon atoms; a′ is 0 to 6; b′ is 0 or 1; c′ is 0 or 1; and d′ is 0 or 1.
A preferred silicone-containing component is represented by the following formula XVIII:
wherein R23 is a diradical of a diisocyanate after removal of the isocyanate group, such as the diradical of isophorone diisocyanate. Another preferred silicone containing macromer is compound of formula XIX (in which x+y is a number in the range of 10 to 30) formed by the reaction of fluoroether, hydroxy-terminated polydimethylsiloxane, isophorone diisocyanate and isocyanatoethylmethacrylate.

In an alternative embodiment of the present invention, the siloxane group-containing monomer may be a material of formula (A) or (B):(T1-Y1)k-G1(Y2—Z)l  (A)[(T1)k-Y3(Z)u]v-G1-R24  (B)wherein                T1 is a polymerisable group;        Y1 and Y2 are each independently a linker group selected from the group consisting of a bond, C1-12 alkylene, C2-12 alkenylene, C2-12 alkynylene, C3-12 cycloalkylene, C3-12 cycloalkenylene, C2-12 heteroalkenylene, C2-12 heteroalkynylene, arylene, heteroarylene, —C(O)—C1-12 alkylene, —C(S)—C1-12 alkylene, —C(O)O—C1-12 alkylene, —C(O)S—C1-12 alkylene, —C(O)N(RM)—C1-12 alkylene, —C(S)—O1-12 alkylene, —C(S)O—C1-12 alkylene, —C(S)S—C1-12 alkylene, —C(S)N(RM)—C1-12 alkylene, —(CH2)qq(OCH2CH2)rr— and —(CH2CH2O)rr(CH2)qq—, wherein RM is hydrogen or C1-4 alkyl, qq is an integer from 1 to 10, rr is an integer from 1 to 10, wherein one or more carbon atoms in the C1-12 alkylene group may be optionally replaced with a heteroatom selected from the group consisting of S and O and the alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, heteroalkenylene, heteroalkynylene, arylene and heteroarylene groups may be optionally substituted with one or more RN, wherein each RN is independently selected from the group consisting of —H, —OH, —CN, —NO2, —CF3, —OCF3, —CO2H, —NH2, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, —O(C1-C10 alkyl), —O(C2-C10 alkenyl), —O(C2-C10 alkynyl), halogen, —C(O)H, —C(O)—(C1-C10 alkyl), —C(O)—O(C1-C10 alkyl), —NH(C1-C10 alkyl), —N(C1-C10 alkyl)2, —C(O)—NH(C1-C10 alkyl), —C(O)—N(C1-C10 alkyl)2, —NH—C(O)—(C1-C10 alkyl), —NH(C1-C10 alkyl)-C(O)—(C1-C10 alkyl), —NH—S(O)2—(C1-C10 alkyl), —NH—(C1-C10 alkyl)-S(O)2—(C1-C10 alkyl), —(C0-C10)—SH, —S(O)—(C1-C10 alkyl), —S(O)2—(C1-C10 alkyl), —S(O)2—NH2, —S(O)2—NH—(C1-C10 alkyl), —S(O)2—N(C1-C10 alkyl)2 and ═O;        Y3 is a linker group;        R24 is a C1-12 alkyl group which may be optionally substituted with one or more RN;        G1 is a siloxane group-containing component;        Z is a zwitterionic group;        k is an integer from 1 to 10;        l is an integer from 1 to 3;        u is an integer from 1 to 3; and        v is an integer from 1 to 3.        
In such embodiments of the present invention, the siloxane group-containing monomer includes a polymerisable group, siloxane functionality and a zwitterionic functionality within the same molecule. This is advantageous because any phase separation may be at a molecular level and so will not be visible to the naked eye. Furthermore, combining the functionalities on a molecular level makes it possible to provide materials which have a higher oxygen permeability than might be expected for a given water content.
Although formula (A) and formula (B) (and the chemical formulae which follow herein) are represented without any indication of specific stereochemistry, the skilled person will understand that a number of isomers are possible. In this regard, the present invention includes within its scope, all possible stereoisomers of the chemical structures depicted.
The polymerisable group T1 is not limited and it may be any group which is capable of reaction under polymerisation conditions to form a polymer. It is the presence of the polymerisable group in the materials of the present invention which means that it is possible to form polymers and, ultimately, contact lenses from the materials of the present invention. In certain embodiments, the polymerisable group includes at least one carbon-carbon unsaturated bond. In such embodiments, the group is capable of addition polymerisation reactions. Alternatively, or in addition, the group which is capable of reaction to form a polymer is a multi-functionalised derivative which is capable of condensation polymerisation. This includes, for example, materials such as diols, diamines, diacids and derivatives thereof.
In one embodiment, the siloxane group-containing monomer is a material of formula (A). In an alternative embodiment, the siloxane group-containing monomer is a material of formula (B).
In one embodiment, the polymerisable group T1 includes a group which is selected from the group consisting of acrylates, methacrylates, acrylamides, methacrylamides, styrenic and vinylic groups. Examples of suitable vinylic groups include allyl derivatives, N-vinyl lactam derivatives, such as suitably substituted N-vinyl pyrrolidone derivatives and N- and O-vinyl derivatives.
In one embodiment, the polymerisable group T1 is a methacrylate or acrylate group. Preferably, the polymerisable group T1 is a methacrylate group.
With reference to formula (A) and formula (B) above, k is an integer which defines the number of polymerisable groups, T1, present in the polymerisable material. k may be 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. Preferably, k is 1 or 2.
Y1 is a linker group which forms a link between the polymerisable group T1 and the siloxane group-containing component, G1, in a polymerisable material of formula (A). Y2 is a linker group which forms a link between the siloxane group-containing component, G1 and the zwitterionic group, Z in a polymerisable material of formula (A). Y1 and Y2 are each independently selected from the group consisting of a bond, C1-12 alkylene, C2-12 alkenylene, C2-12 alkynylene, C3-12 cycloalkylene, C3-12 cycloalkenylene, C2-12 heteroalkenylene, C2-12 heteroalkynylene, arylene, heteroarylene, —C(O)—C1-12 alkylene, —C(S)—C1-12 alkylene, —C(O)O—C1-12 alkylene, —C(O)S—C1-12 alkylene, —C(O)N(RM)—C1-12 alkylene, —C(S)—C1-12 alkylene, —C(S)O—C1-12 alkylene, —C(S)S—C1-12 alkylene, —C(S)N(RM)—C1-12 alkylene, —(CH2)qq(OCH2CH2)rr— and —(CH2CH2O)rr(CH2)qq—, wherein RM is hydrogen or C1-4 alkyl, qq is an integer from 1 to 10, rr is an integer from 1 to 10, wherein one or more carbon atoms in the C1-12 alkylene group may be optionally replaced with a heteroatom selected from the group consisting of S and O and the alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, heteroalkenylene, heteroalkynylene, arylene and heteroarylene groups may be optionally substituted with one or more RN, wherein each RN is independently selected from the group consisting of —H, —OH, —CN, —NO2, —CF3, —OCF3, —CO2H, —NH2, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, —O(C1-C10 alkyl), —O(C2-C10 alkenyl), —O(C2-C10 alkynyl), halogen, —C(O)H, —C(O)—(C1-C10 alkyl), —C(O)—O(C1-C10 alkyl), —NH(C1-C10 alkyl), —N(C1-C10 alkyl)2, —C(O)—NH(C1-C10 alkyl), —C(O)—N(C1-C10 alkyl)2, —NH—C(O)—(C1-C10 alkyl), —NH(C1-C10 alkyl)-C(O)—(C1-C10 alkyl), —NH—S(O)2—(C1-C10 alkyl), —NH—(C1-C10 alkyl)-S(O)2—(C1-C10 alkyl), —(C0-C10)—SH, —S(O)—(C1-C10 alkyl), —S(O)2—(C1-C10 alkyl), —S(O)2—NH2, —S(O)2—NH—(C1-C10 alkyl), —S(O)2—N(C1-C10 alkyl)2 and ═O. Y1 and Y2 may be the same or different. In one embodiment, Y1 and Y2 are the same. In an alternative embodiment, Y1 and Y2 are different.
In one embodiment, Y1 and Y2 are each independently a C1-12 alkylene group. In an alternative embodiment, Y1 is a group of formula —(CH2)q(OCH2CH2)r— and Y2 is a group of formula —(CH2CH2O)rr(CH2)qq—, wherein IT is an integer in the range from 1 to 10, preferably 4 to 6 and qq is an integer in the range from 1 to 10, in one embodiment, 2 to 4, preferably 3.
Y3 is a linker group which forms a link between the polymerisable group, T1 and the siloxane group, G1, in polymerisable material of formula (B). In this embodiment of the present invention, the zwitterionic group, Z, is a substituent on the linker group, Y3. The nature of Y3 is not particularly limited and in a preferred embodiment, Y3 is selected from the group consisting of a bond, C1-12 alkylene, C2-12 alkenylene, C2-12 alkynylene, C3-12 cycloalkylene, C3-12 cycloalkenylene, C1-12 heteroalkylene, C2-12 heteroalkenylene, C2-12 heteroalkynylene, arylene, heteroarylene, —C(O)—, —C(S)—, —C(O)O—, —C(O)S—, —C(O)N(RM)—, —C(S)—, —C(S)O—, —C(S)S— and —C(S)N(RM)—, wherein RM is hydrogen or C1-4 alkyl. The alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, heteroalkylene, heteroalkenylene, heteroalkynylene, arylene and heteroarylene groups may be optionally substituted with one or more RN, wherein each RN is independently selected from the group consisting of —H, —OH, —CN, —NO2, —CF3, —OCF3, —CO2H, —NH2, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, —O(C1-C10 alkyl), —O(C2-C10 alkenyl), —O(C2-C10 alkynyl), halogen, —C(O)H, —C(O)—(C1-C10 alkyl), —C(O)—O(C1-C10 alkyl), —NH(C1-C10 alkyl), —N(C1-C10 alkyl)2, —C(O)—NH(C1-C10 alkyl), —C(O)—N(C1-C10 alkyl)2, —NH—C(O)—(C1-C10 alkyl), —NH(C1-C10 alkyl)-C(O)—(C1-C10 alkyl), —NH—S(O)2—(C1-C10 alkyl), —NH—(C1-C10 alkyl)-S(O)2—(C1-C10 alkyl), —(C0-C10)—SH, —S(O)—(C1-C10 alkyl), —S(O)2—(C1-C10 alkyl), —S(O)2—NH2, —S(O)2—NH—(C1-C10 alkyl), —S(O)2—N(C1-C10 alkyl)2 and ═O. The position of the group Z as a substituent of the linker group Y3 is not limited. In this regard, the group Z may be a substituent on any one of the carbon atoms which form a part of the backbone of the linker group, Y3.
In one embodiment, Y3 is a C1-12 alkylene or heteroalkylene group, in particular a heteroalkylene group of formula —(CH2)qq(OCH2CH2)n— or —(CH2CH2O)rr(CH2)qq—, wherein qq is an integer from 1 to 10 and rr is an integer from 1 to 10. In a preferred embodiment, Y3 is —(CH2)3—O—(CH2)3—. In a preferred embodiment of the present invention, the position of substitution of the Z group on the Y3 group is such that the group —Y3(Z)— is —(CH2CH(Z)CH2)—O—(CH2)3—.
G1 is the siloxane group-containing component of the siloxane-group containing monomer of this embodiment. As described previously, it is the inclusion of the siloxane functionality in the siloxane group-containing monomer which provides a material which has good gas permeability. The nature of the siloxane group-containing component is not particularly limited and the skilled person will be familiar with suitable components. A siloxane group is one which includes the residue having the general structure —[Si(R)2O]—, wherein each R is independently selected from hydrogen or a C1-12 alkylene, C2-12 alkenylene, C2-12 alkynylene, C3-12 cycloalkylene, C3-12 cycloalkenylene, C1-12 heteroalkylene, C2-12 heteroalkenylene, C2-12 heteroalkynylene, arylene, heteroarylene group, optionally substituted with one or more RN, wherein each RN is independently selected from the group consisting of —H, —OH, —CN, —NO2, —CF3, —OCF3, —CO2H, —NH2, C1-C10 alkyl, C2-C10 alkenyl, alkynyl, —O(C1-C10 alkyl), —O(C2-C10 alkenyl), —O(C2-C10 alkynyl), halogen, —C(O)H, —C(O)—(C1-C10 alkyl), —C(O)—O(C1-C10 alkyl), —NH(C1-C10 alkyl), —N(C1-C10 alkyl)2, —C(O)—NH(C1-C10 alkyl), —C(O)—N(C1-C10 alkyl)2, —NH—C(O)—(C1-C10 alkyl), —NH(C1-C10 alkyl)-C(O)—(C1-C10 alkyl), —NH—S(O)2—(C1-C10 alkyl), —NH—(C1-C10 alkyl)-S(O)2—(C1-C10 alkyl), —(C0-C10)—SH, —S(O)—(C1-C10 alkyl), —S(O)2—(C1-C10 alkyl), —S(O)2—NH2, —S(O)2—NH—(C1-C10 alkyl), —S(O)2—N(C1-C10 alkyl)2 and ═O. The R groups may be the same or different. In one embodiment all of the R groups are the same. In an alternative embodiment, the R groups are different. Preferably R is a C1-12 alkylene group, preferably a C1-6 alkylene group. Preferably, the Si and attached 0 are present in the siloxane group in an amount greater than 20 weight percent, and more preferably greater than 30 weight percent of the total molecular weight of the siloxane group-containing component.
In one embodiment, the siloxane group-containing component has the formula (a):
wherein R is as defined previously and w is an integer from 1 to 500.
In one embodiment, the siloxane group-containing component has the formula (b):
wherein R is as defined previously and w1 and w2 are independently an integer in the range from 1 to 500.
In one embodiment, the siloxane group-containing component has the formula (c):
wherein R is as defined previously and w3, w4 and w5 are each independently an integer in the range from 1 to 500.
In one embodiment, the siloxane group-containing component has the formula (d):
wherein R is as defined previously and w6, w7, w8 and w9 are each independently an integer in the range from 1 to 500.
Z is a zwitterionic group as defined previously. Where the siloxane group-containing monomer has formula (A), Z is bonded to Y2. Where the siloxane group-containing monomer has formula (B), Z is a substituent on the linker group Y3.
Preferably, Z is a group of formula (IVB), in particular, a group of formula (IVB), wherein all R4 groups are methyl groups and b is 2. In this embodiment, the zwitterionic group is a phosphorylcholine (PC) group.
l is an integer which defines the number of zwitterionic groups which are present in the siloxane group-containing monomer of formula (A). l may be 1, 2 or 3. Preferably, l is 1 or 2.
u is an integer which defines the number of zwitterionic groups which are present in the siloxane group-containing monomer of formula (B). u may be 1, 2 or 3. Preferably, u is 1 or 2.
v is an integer which defines the number of [T1)k-Y3(Z)u] groups which are present in the siloxane group-containing monomer of formula (B). u may be 1, 2 or 3. Preferably, u is 1 or 2.